Hydrogenation of Arenesfor Organic Synthesis

Literature Seminar #3

2020/10/23

M2 Yuki Hirao

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Catalytic Hydrogenation

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Hydrogenation of Arenes

Coord. Chem. Rev. 2016, 314, 134.

Aromatic Stabilization Energy (ASE) contributes to the greater resistance by hydrogenation.

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Application

Industrial Application Material Science

Natural Product Medicinal Chemistry

Angew. Chem. Int. Ed. 2019, 58, 10460.

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Challenges

Reactivity

Stereoselectivity Chemoselectivity

The hydrogenation of arenes is hindered by the

added kinetic barrier resulting from the

aromatic stabilization energy.

The hydrogenation of multisubstituted arenes

may form several diastereomers.

Substituted saturated carbo- & heterocycles are

often chiral.

Elaborate substrates often exhibit competing

side reactions.ex.) more reductively labile

units, such as carbonyls, hydrodefunctionalizations

Angew. Chem. Int. Ed. 2019, 58, 10460.

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Contents

1. Introduction

2. Stereoselectivity・diastereoselectivity・enantioselectivity

3. Chemoselectivity・FG tolerance・mechanistic investigation

4. Summary

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cis-Selectivity

Arene hydrogenation generally proceeds with high cis selectivity.

cis isomer vs trans isomerkinetically thermodynamically

The formation of the trans isomer requires a π-facial exchange (catalyst dissociation-reassociation process).

✓Hydrogenation of dearomatized intermediates should be faster than that of stabilized aromatic substrate.

✓The catalyst would have to bind to the sterically more hindered π-face.

RSC Adv. 2016, 6, 18419.

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Enantioselectivity

Chem. Rev. 2012, 112, 2557.

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Chiral Auxiliary

Angew. Chem. Int. Ed. 2004, 43, 2850.

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Chiral BrØnsted Acid Catalyst

Angew. Chem. Int. Ed. 2006, 45, 3683.

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Chiral Ligand

Angew. Chem. Int. Ed. 2019, 58, 10460.

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Application in Total Synthesis

B. M. Stoltz et al. Science 2019, 363, 270.

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Retrosynthesis of (-)-Jorumycin

B. M. Stoltz et al. Science 2019, 363, 270.

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Enantio- & Diastereoselective Hydrogenation

B. M. Stoltz et al. Science 2019, 363, 270.

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Catalyst Screening

B. M. Stoltz et al. Science 2019, 363, 270.

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Short Summary

Angew. Chem. Int. Ed. 2019, 58, 10460.

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Contents

1. Introduction

2. Stereoselectivity・diastereoselectivity・enantioselectivity

3. Chemoselectivity・FG tolerance・mechanistic investigation

4. Summary

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Chemoselectivity | FG tolerance

Challenges

1. Other reducible sites

2. Hydrodefunctionalization

3. Sterically hinderance

4. Negative influence in electronical properties

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Phenol Hydrogenation to Cyclohexanone

T. Jiang, B. Han et al. Science 2009, 326, 1250.

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Aromatic Carbonyl Compounds

X. Zeng et al. J. Am. Chem. Soc. 2015, 137, 9250.

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Substrate Scope

X. Zeng et al. J. Am. Chem. Soc. 2015, 137, 9250.

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Hydrogenation of Fluoroarenes

F. Glorius et al. Science 2017, 357, 908.

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Reaction Optimization

F. Glorius et al. Science 2017, 357, 908.

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Substrate Scope

F. Glorius et al. Science 2017, 357, 908.

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Mechanistic Experiments

F. Glorius et al. Science 2017, 357, 908.

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Deuterium-Labeling Experiments

X. Zeng et al. Angew. Chem. Int. Ed 2019, 58, 16785.

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Fluoropyridines

F. Glorius et al. Nat. Chem. 2019, 11, 264.

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Dearomatization Strategy

T. Ohmura, M. Suginome et al. J. Am. Chem. Soc. 2012, 134, 3699.F. Glorius et al. Nat. Chem. 2019, 11, 264.

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Substrate Scope

F. Glorius et al. Nat. Chem. 2019, 11, 264.

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Application

F. Glorius et al. Nat. Chem. 2019, 11, 264.

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Contents

1. Introduction

2. Stereoselectivity・diastereoselectivity・enantioselectivity

3. Chemoselectivity・FG tolerance・mechanistic investigation

4. Summary

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Sillica gel improves the reactivity

F. Glorius et al. Angew. Chem. Int. Ed 2018, 57, 8297.

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Catalyst Poisoning Study

F. Glorius et al. ACS Catal. 2020, 10, 6309.

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Catalyst Filtlation & Rycycling

F. Glorius et al. ACS Catal. 2020, 10, 6309.

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Kinetic Study

F. Glorius et al. ACS Catal. 2020, 10, 6309.

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Observation of Ligand

F. Glorius et al. ACS Catal. 2020, 10, 6309.

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Comparing the Performance

F. Glorius et al. ACS Catal. 2020, 10, 6309.

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Summary

F. Glorius et al. ACS Catal. 2020, 10, 6309.

Silica gel-supported Rh(0) NPs as active catalytic species

CAAC-derived pyrrolidium and pyrrolidine act as modifiers that are key in controlling the chemoselectivity.

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Summary

Functionalization of arene is more facile than that of the saturated products.